Heavy Metal

“Metals are very powerful,” says Rachel Narehood Austin, the Diana T. and P. Roy Vagelos professor of chemistry and chair of Barnard’s chemistry department. “Their effects are not at all subtle.” As a bioinorganic chemist — a scientist who studies the role of metals in biology — she should know. A year or so after Austin came to Barnard in 2015, she and her fellow Barnard chemists Mary Sever and Christina Vizcarra, both assistant professors, along with their students, began working together to understand the impact on the brain of one very powerful metal, the biological bully known as lead.

Unlike other metals, such as iron and calcium, which perform many vital roles in human biology, lead serves no purpose there. When children ingest even tiny amounts of it, from sources such as peeling paint, food grown in contaminated soil, and contaminated water, the metal can have lifelong effects. These children are at increased risk for slowed growth and development, brain- and nervous-system damage, and learning and behavior problems such as reduced IQ, attention deficits, and criminal behavior. Recent research links childhood lead exposure to complex brain diseases in adulthood, including Alzheimer’s, Parkinson’s, and schizophrenia.

Nationwide, approximately 2 percent of small children have dangerously high levels of lead in their blood, according to the federal Centers for Disease Control and Prevention. And children living below the poverty line are four times more likely to experience lead poisoning than children living above it. Flint, Michigan, where corrosive river water leached lead from pipes into the city’s households, may be the most widely reported example of lead’s dangers. But it’s far from the only one. Nearly 3,000 locales across the country have lead poisoning levels at least double those of Flint. And in many of those neighborhoods, lead levels were at least four times as high. “Tiny amounts of lead,” says Austin, “can change the whole trajectory of a toddler’s intellectual development.” These three Barnard chemists, recipients of a $294,000 grant from the National Science Foundation to study the problem, are hoping to help find out how this phenomenon occurs.

Austin began this research after a friend, a chemist, recommended taking a look at how lead interacts with proteins called metallothioneins. These small compounds grab onto charged metal atoms called ions and hold them tight. In mammals, the proteins are thought to deliver essential metals to the places where they belong in the body, and to “sop up” toxic metals, Austin explains.

The most common form of lead ion has a similar size and the same charge as the most common forms of zinc ions and calcium ions. That allows lead to substitute for them in important proteins and disrupt their function.

As Austin began her research, she zeroed in on a particular form of metallothionein: metallothionein-3 (MT3), a mysterious protein that occurs primarily in the brain. One study showed that people with Alzheimer’s disease had lower concentrations of MT3 in their brains than did their healthy counterparts. MT3 has also been shown to reduce the toxic effects of amyloid beta, a chemical that forms sticky plaques in the brains of people with the illness. Experimenting with MT3, Austin found that the protein binds more tightly to lead than to zinc. She wondered whether lead could disrupt MT3’s normal function in the brain by displacing zinc, causing the protein to interact differently with other proteins.

When Austin arrived at Barnard almost four years ago, Sever was already studying the impacts of metals on brain cells, examining how copper and iron affect gene expression — the process of turning a cell’s genetic “blueprint” into actual proteins. Vizcarra was working on another piece of their puzzle, studying actin, a protein that can be assembled into sticklike structures that function like an Erector Set. Actin is abundant in most human cells and is vital for their internal structure, the cytoskeleton. “So I come to this collaboration, really,” Vizcarra explains, “because Rachel and Mary came to me and said this protein we’re studying, MT3, interacts with actin.”

Following up on clues in previous work, the three chemists hypothesize that in normal cells, the ways MT3 binds to actin help determine how the cell’s cytoskeleton will grow. However, when MT3 binds in the brain to lead instead of to its normal metal ions, zinc or copper, the cytoskeleton can’t form correctly, potentially leading to some of the alterations in the brain associated with lead exposure. The chemists are working to test these hypotheses in the lab.

In other experiments, they’ve been looking at whether cells would produce different amounts of MT3 in response to metals. The chemists expected to find MT3 levels affected by the amount of metal ions present, as was the case with other metallothioneins. But to their surprise, that’s not what their experiments showed. MT3 was special; something different was going on.

Now, in a new line of inquiry, they’re testing the hypothesis that MT3 levels are impacted by low oxygen content in the cells, a condition called hypoxia. Because hypoxia occurs in cells in certain well-known pathologies, such as stroke, this might provide a hint as to what biological job MT3 normally performs in the brain and how lead interrupts that function.

In addition to the chemistry they study in the lab, the three scientists display an obvious chemistry with one another. They elaborate on one another’s points, praise one another’s skills, and burst into simultaneous laughter. Sever says their collaboration clicked because “I had been looking at how Alzheimer’s might be influenced by something like copper levels, excess metals that are already present in the brain. And then you,” she says to Austin, “came in with this idea of lead, which is not a metal that’s commonly present in the brain but is something that’s medically relevant. And you had a system ready to go, metallothionein, that you’d already been working on. It was just a matter of applying the things that we normally do in our lab to a new protein, with a new metal.”

Says Vizcarra, “One really great thing about this collaboration is that it spills over to the students,” helping them see the big picture. The three principal investigators work with a group of undergraduates they describe as enthusiastic and committed.

As scientists, the three investigators agree that they’re very similar in temperament: meticulous and cooperative. “I couldn’t have asked for better collaborators,” Austin says. “Together, we can ask much more interesting questions than the ones I was capable of asking and answering on my own” — questions that the three chemists hope will motivate policymakers to take action against the dangerous metal lead. •

Polly Shulman is a staff writer at the American Museum of Natural History.